Water-soluble corticoid compounds that decompose in plasma or tissue fluid with liberation of a free corticoid;and process of producing said compounds



United States Patent Office 3,513,177 Patented May 19, 1970 WATER-SOLUBLE CORTICOID COMPOUNDS THAT DECOMPOSE IN PLASMA OR TISSUE FLUID WITH LIBERATION OF A FREE CORTICOID;

AND PROCESS OF PRODUCING SAID COM- POUNDS Carl Emil Vermehren and Thomas Ludvig Martin Vermehren, both of 8 Wiedersvej, Dragor, Denmark No Drawing. Filed Apr. 6, 1966, Ser. No. 540,528 Int. Cl. C07c 167/28 US. Cl. 260-397.45 3 Claims ABSTRACT OF THE DISCLOSURE Monoalkali metal and monoammonium salts of di-corticord phosphates have the peculiar property that under certain circumstances they are able to react with free corticoids to form water-soluble compounds therewith whereby the solubility increases 300 to 600 times that of nonreacted corticoids and, in all cases tried, reaches a value of more than 0.2 mg. per ml., which allows the admission of therapeutic doses by way of injection of one or a few milliliters of water; and the bond secured is of loose character clearly demonstrated by removal of the free corticoid quantitatively upon shaking with water.

The invention concerns water-soluble corticoid compounds that decompose instantaneously in plasma or tissue fluid with liberation of corticoid in free form. Furthermore the invention concerns a method of producing said compounds. The compounds in question are especially effective for treating shock and shock-like conditions.

It is known to apply corticoids effective against said conditions, such as hydrocortisone and cognate substances in the form of an alcoholic suspension of a free corticoid mixed with aqueous infusion liquids, to be administered intravenously by infusion when a quick effect had to be obtained. However, the administration of medicines in the form of infusions has the drawback that special equipment is necessary for carrying out the infusion, which ordinarily necessitates that the patient be hospitalized. Furthermore, carrying out the preparatory measurements for the infusion is time consuming and the infusion process itself takes a long time, in most cases at least a couple of hours.

In order to avoid such drawbacks water-soluble corticoid compounds have been produced, ordinarily in the form of esters, the solubility of which is sufficient to make it possible to introduce in the patient the necessary amount of corticoid by injecting a small volume, for in stance 1 ml. of a liquid in which it is contained. In many cases such injections may be given intravenously. Consequently the medicament can be brought into the blood stream and distributed therein in the course of a few minutes after the patient has been brought under the care of a doctor. However, this mode of administration has the drawback that the compounds in question are true chemical derivatives which must be decomposed in the organism to split off the free corticoid before the effect takes place. The process is an enzymatic one caused by substances, for instance esterases, present in the blood stream. Consequently a considerable time passes until the injected amount of corticoid has been converted into a form in which it is available to the organism.

It would be desirable to have water-soluble corticoids which would split off instantanously the effective corticoid on injection into the blood circulation, so that the effect would be instantaneous.

It has now been found that monoalkali metal and monoammonium salts of di-corticoidphosphates have the peculiar property that under certain circumstances they are able to react with free corticoids to form Water-soluble compounds therewith. Hereby the solubility increases to 300600 times the solubility of non-reacted corticoids and in all cases tried, reached a value of more than 0.2 mg. per ml., which is sufficient to allow the administration of therapeutic doses by way of injection of one or a few milliliters of water. The bond, by which this increased solubility has been secured is, however, of a somewhat loose character which is clearly demonstrated, i.e.., by the fact that the free corticoid may be removed quantatively from the compound by shaking an aqueous solution of the compound with water.

The character of the binding is not known, and it is unsure whether it takes place in fixed stoichiometrical proportions or not.

According to the invention such water-soluble corticoid compounds which in plasma or tissue fluid are split up instantaneously while giving off free corticoid are produced by contacting an aqueous solution of mono-alkalimetal salt of di-corticoidphosphate or a corresponding ammonium salt with a solution of corticoid in a solvent which is at least partly miscible with water.

Hereby the desired product is obtained which when injected is found to have an instaneous effect corresponding to the amount of free corticoid used for the preparation. The amount of corticoid used as phosphate is liberated gradually in the organism. Consequently the preparation is very well suited for use in the treatment of shock or shock-like conditions.

According to a preferred embodiment of the invention the reaction mixture is transformed into a homogeneous solid state in which it is stable which is shown by the fact that it dissolves to form clear solutions at the abovementioned high and in some cases even higher concentrations, which solutions when used for injections show the abovementioned effect.

According to a further preferred embodiment of the invention the transformation of the reaction mixture into a homogeneous solid state takes place by freeze-drying, so-called, i.e., a drying process at such low temperature that the reaction mixture stays solid. It has been found that the mixture stands the freezing very well and that the product obtained when adding thereto the amount of water necessary to form a concentrated solution dissolves spontaneously to form a clear liquid which may be injected intravenously.

It has further been found that the 21-phosphates of corticoids may be used for the di-steroid-phosphate, and in connection herewith the same or another corticoid in free form may be used, subject to the condition that it has a hydroxyl group in the 11- or the 21-position. Exactly these corticoids are generally well suited for the treatment of shock or shock-like conditions.

Experiments have been carried out with salts of dihydrocortisone-21-phosphate and of di-prednisolone-Zlphosphate, but also the mono-salts of other di-corticoidphosphates are assumed to be effective. By Way of example corticosterone, hydrocortisone, prednisolone and dexamethazone are mentioned as substances which when used for the free steroid component have shown the effect described above, but substitution derivatives are supposed to work in the same manner. In contrast thereto the effect does not take place when other steroids such as oestradiol, progesterone or testosterone are used. The effect does not either take place if the corticoid or the corticoidphosphate is simply dried.

As solvent for the steroid component any solvent or mixture of solvents which is suitable for dissolving the corticosteroid in question can be used, provided that it is partly or completely miscible with water. By way of examples of such solvents may be mentioned ethanol, methanol, dioxane, pyridine, mixtures of pyridine and benzene, dimethylformamide and many others. Care must be taken that during the conversion of the reaction mixture into solid state no separation of solid steroid takes place. Such separation can inany case be easily avoided when said sensitive enough for registering it after 60 minutes. The analytic method used is: J. van der Vies, Acta Endocrinologica 38, 399 (1961).

Pigs Weighing 25-30 kgs. were brought into ether-nembutal narcosis until shock-condition started. The abdomen conversion takes place by way of freeze-drying. was opened and it could be seen that the peristaltic move- The amount of the steroid in proportion to the amount ment had ceased and that the colour of the intestines of the phosphate may be varied within wide limits, in was cyanotic. By intraveneously injecting 100 mg. of the any case within the limits 1 to 3 mol steroid per mol same addition compound as mentioned above in 1 ml. of steroidphosphate. However, amol ratio of about 1:1 seems water, the peristaltic movement started again 30-60 secto be especially well suited. With increasing contents of onds after the injection and the intestines again assumed free corticoid ditficulties with the freeze-drying process their normal colour. may be encountered, since increased contents of corticoid What is claimed is: in the mixture necessitates higher concentrations of organic 1. Process of producing water-soluble corticoid comsolvents, whereby the freezing temperature is decreased. positions which decompose instantaneously into plasma or EXAMPLE tissue fluid with liberation of corticoid in free form, which comprises reacting an aqueous solution of a substance of 1% solutions of the corticoids mentioned below in the class consisting of the monoalkali metal salt of dicortiorganic solvents are mixed with 1% solutions of di-hydrocoid phosphate and the ammonium salt of dicorticoid phoscortisonephosphate-monosodium salt in water in the ratios phate with a solution of corticoid in a solvent which is at stated, which correspond to the mol ratio 1:1, whereleast partly miscible with water, hydrocortisone and predupon the mixtures are freeze-dried. nisolone as dicorticoid phosphate, and hydrocortisone,

Solubility Steroid in water of solubility the mixed Solvent for Percent Percent in water compound Steroid the steroid steroid ester (mg/ml.) (mg/ml.)

Cortico-sterone... Ethanol"..- 30.0 70. 0 0. 2 200 Hydrocortlsone Methanol 31.0 69.0 0. 2 200 Prednisolone Dioxane 30. 8 69. 2 0. 2 200 Dexamethazon Pyrldine 32.7 67.3 0.2 200 Corresponding compounds may be produced by substiprednisolone and dexamethazone as free steroids, being tuting di-prednisolone phosphate monosodium salt for the employed, and transferring the reaction mixture into di-hydrocortisone phosphate monosodium salt. The soluhomogeneous solid state. bility of the addition compound hereby surpasses 50 mg./ 2. Process according to claim 1 wherein the reaction ml. in all cases tried. mixture is subjected to freeze-drying.

By injection in rats weighing 250 g. of the addition com- 3. Process according to claim 2 wherein the phosphate pound mentioned in the above example, consisting of 31% is a 21-phosphate and the corticoid used in its free form hydrocortisone and 69% di-hydrocortisone phosphate has a hydroxyl group either at the 11- or 2l-position. monosodium salt, in an amount of 0.5 mg. dissolved in 1 ml. of water the following concentrations of hydrocorti- References Cited some in the plasma were found in 'y/mL:

Time after injection: 'y/100-30 sec., 136; 5 min., 80; FOREIGN T E 0 min., 2 5; i 0. Great Bl'ltaln.

Whereas injection of 0.35 mg. di-hydrocortisone phos- 826,385 1/1960 Great Bntam' phate monosodium salt dissolved in 1 ml. of water did not OTHER REFERENCES produce ascertainable hydrocortisone contents in the a plasma during the experiment period. This shows that the fgL ggf i g of Japan 181 (1961) loosely bound hydrocortison is liberated immediately re upon the injection whereas the ester-bound hydrocortisone is so slowly liberated that the analytic method used is not ELBERT L. ROBERTS, Primary Examiner 

